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Vet Clin North Am Small Anim Pract. Author manuscript; available in PMC 2015 November 01.
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Vet Clin North Am Small Anim Pract. 2014 November ; 44(6): 1113–1129. doi:10.1016/j.cvsm.
2014.07.008.
Aging in the Canine and Feline Brain

Charles H. Vite, DVM, PhDa and Elizabeth Head, MA, PhDb,*
aDepartment of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania,
Section of Neurology & Neurosurgery, Department of Clinical Studies - Philadelphia, 3900
Delancey Street, Philadelphia, PA 19104, USA
bDepartment of Pharmacology & Nutritional Sciences, Sanders-Brown Center on Aging,
University of Kentucky, 800 South Limestone Street, 203 Sanders Brown Building, Lexington, KY
40515, USA
Keywords
β-Amyloid; Cat; Dog; Cognitive dysfunction; Neuron loss; Tau
INTRODUCTION
This article reviews canine and feline brain aging. Several key features are discussed and
compared, including general aging characteristics and neuropathology. Aging dogs and cats
show many similarities in terms of brain changes but also some important differences.
Several research groups have been working with aging dogs and cats to test various theories
of aging and to develop therapeutics that will be beneficial to both species.
The median life span of dogs varies as a function of breed, with larger breeds typically
having shorter life spans than smaller breeds.1–3 For the purposes of this article, several
studies that are described have been collected in purpose-bred beagles and additional
companion animals and clinical data are shared when available. Beagles have a median life
span of 13.9 years, with no significant differences between males and females.4 A young
beagle less than 5 years old is similar to humans who are less than 40 years old.3 Middle-
aged beagles between 5 and 9 years are similar to humans between 40 and 60 years and
beagles more than 9 years old are similar to humans more than 60 years old. However, the
larger the breed of dog, the shorter the life span and thus biological age may vary across
breeds given a specific age.1
In a laboratory setting and in the veterinary clinic, studies of aging dogs report that some but
not all aged dogs are impaired on different measures of learning and memory (see Refs.5–7).
Not all old dogs are impaired and not all types of learning and memory are equally affected.
Neurobiological changes, as described later, can account for some, but not all, of the clinical
signs of cognitive decline in aging dogs.
© 2014 Elsevier Inc. All rights reserved.

*
Corresponding author. elizabeth.head@uky.edu.
Vite and Head Page 2
NEUROBIOLOGY OF AGING IN THE DOG

This article describes several neurobiological changes associated with aging in dogs (Table
1).
Brain Atrophy
Old dogs often show marked ventriculomegaly at postmortem examination associated with
thinning of the cerebral cortex and the subcortical white matter.8 Magnetic resonance
imaging (MRI) studies performed on aged beagle and German shepherd dogs show that
cortical atrophy, identified as widened sulci, thinned parenchyma,9 and ventricular
dilatation,9–11 progresses with age and is a consistent feature of canine brain aging.
Furthermore, MRI studies suggest differential vulnerabilities of specific brain areas to aging.
For example, in aging beagle dogs, the prefrontal cortex loses tissue volume at an earlier age
(approximately 8–11 years) than does the hippocampus (after 11 years).12 An MRI study by
Hasegawa and colleagues13 (2005) suggested that although interthalamic adhesion thickness
was smaller in older dogs, those showing age-related cognitive decline and a single dog with
GM1 gangliosidosis also had a significant decrease in the thickness.
Periventricular white matter signal abnormalities are frequently seen in MRI of various dog
breeds greater than 12 years of age that are evaluated for seizures, vestibular disease, or
behavioral abnormalities. These bilaterally symmetric T2-weighted hyperintensities of the
internal capsule are suspected to be caused by wallerian degeneration, demyelination, and
accompanying gliosis.14
Selective Neuron Loss

Atrophy may result from neuron loss or changes in neuronal density, as reported in normal
human brain aging,15,16 although more extensive neuronal loss occurs in Alzheimer disease
(AD).17,18 When neurons were counted using unbiased stereological methods within
individual subfields of the hippocampus of young (3.4–4.5 years) and old (13.0–15.0 years)
dogs, the aged dogs had significantly (~30%) fewer neurons in the hilus of the dentate
gyrus.19 A study by Pugliese and colleagues20 (2007) showed that cognitive deficits
correlated with loss of Purkinje cells in the cerebellum. More recently, a study by Insua and
colleagues21 (2010) examined noradrenergic neurons in the locus coeruleus of aged canines,
a group of neurons that are implicated in AD in humans.22,23 Dogs that are cognitively
impaired show a significant reduction in noradrenergic neurons. Reduced neurogenesis in

the mature brain may also contribute to reduced neuron numbers and age-associated
cognitive decline, resulting in slower replacement of dying neurons. In the hippocampus of
beagles, a 90% to 95% decline in neurogenesis was measured in aged dogs.24 Similar
reductions in neurogenesis in aged dogs have been reported by other investigators.25
Senile Plaques (β-Amyloid) in Dogs

A key feature of canine brain aging was the observation in 1956, by Braumühl, who reported
Alzheimer-like senile plaques in aged dogs (reviewed in Ref.26). Senile plaque accumulation
in the aged canine brain has been well described.26 Senile plaques are composed of β-
amyloid (Aβ) protein, and are one of 2 key types of neurologic pathologies observed in the
AD brain.27 The Aβ peptide is produced by the sequential cleavage of the amyloid precursor
protein (APP) by beta-secretase and gamma-secretase.28,29 Cleavage by gamma-secretase
results in differing lengths of Aβ, with the 42 amino acid form, Aβ1-42 making up most of
the insoluble deposits found in the AD brain.30 One of the reasons why the canine brain has
been examined extensively for Aβ neurologic disorder is that dogs and humans share an
identical amino acid sequence of the protein.31,32 Aβ is thought to be a causative factor for
AD in people.33 The observation of brain Aβ first stimulated interest in the use of the dog to
model human aging and disease.34 Diffuse plaques are the predominant subtype of Aβ in the
aging dog brain (Fig. 1).35–40 Specific brain regions are differentially vulnerable to
Aβ.36,41–46 When cortical regions are sampled for Aβ deposition, each region shows a
different age of Aβ onset.43 In the dog, Aβ deposition occurs earliest in the prefrontal cortex
(see Fig. 1C, D) and later in the temporal cortex, hippocampus (see Fig. 1A, B), and
occipital cortex.45
Beagles that show learning and memory impairments in a laboratory setting with systematic
cognitive tests also show higher levels of Aβ plaques than those old dogs without cognitive
impairments.47–50 For example, dogs with prefrontal cortex–dependent reversal learning
deficits show significantly higher amounts of Aβ in this brain region.48,49 As in laboratory
beagles, the extent of Aβ plaques varies as a function of age in companion dogs (including a
wide variety of breeds and mixed breeds).50–52 Further, the extent of Aβ plaques correlates
with behavior changes and this association remains significant even if age is removed as a
covariate.47,50 Case report 1 and Figs. 1 and 2 show a case study of cognitive decline and
age-associated Aβ neurologic disorder in a border collie.
Case report 1
Martha was a female border collie that was a very competent farm dog with what her
owner called “lots of sheep savvy.” She was also a fully integrated family member and
companion to the family when hiking, skiing, and mountain biking. In addition, she
successfully competed in sheep dog trials till the age of 10 years (see Fig. 1A). She and
her handler worked their way through the succession of novice-level trials, winning
several, and ultimately competing and placing in the highest level, the Open class, which
attests to her skill (see Fig. 1B).
By the time Martha was 11 years old she was nearly deaf and slow enough that she could
no longer trial. She started to show some confusion with commands at which she was
expert. For example, one day her owner took her out in the field and gave her a command
to go counter clockwise around the sheep and she went clockwise. Further, when her
owner next said “OK, go clockwise” she reversed her direction, when she should have
continued the clockwise direction (see Fig. 1C). The next time her owner was working
with her, a normally benign ewe turned around to face Martha and stomped her foot.
Martha, who would normally have politely stood her ground until the sheep backed
down, promptly turned away and left the field. The owner at this time thought, “Well that
is proof that Martha is fully retired now.” Not long after the incident with the ewe, the
sheep began to act as if Martha did not even exist.
Over the next 2 years, changes in Martha were subtle and included increasing hearing
loss and stubbornness. She also stopped having interest in the sheep, and appeared most
fixated with another dog (Ida) in the family. Several behaviors with the other dog
appeared abnormal. For example, Martha would stare at Ida, the middle dog, whether
they were inside or out walking, and then would stalk Ida, despite a lack of interest from
Ida in interacting. The owners had to intervene frequently to prevent a snarling episode,
although the two dogs never injured each other.
To her last day, Martha’s social skills with human friends persisted. However, she began
pacing, panting, and getting stuck under the bedside table at night. During the day when
only 1 of the owners was home, Martha was frequently anxious and sometimes clingy,
which never used to be the case. She showed signs of disorientation and during walks
occasionally lost the younger dogs and her owner although the same daily route was
followed. Martha was once found in a road looking up and down as if lost, although she
had been walking that direction for years.
Throughout her life Martha had a great appetite and generally excellent health, although
she had arthritis in almost every joint in her body and was on high doses of incontinence
medication and Rimadyl (a nonsteroidal antiinflammatory drug) for arthritis. For the last
year of her life, the owner was unable to get a photograph of Martha looking at her
because she was no longer making eye contact (see Fig. 1D).
When Martha was 14 years old, the decision was made to euthanize her and the owner
donated her brain to the University of Kentucky to determine whether neurologic
disorder was present. Aβ neurologic disorder was extensive in Martha (see Fig. 2).
The focus in AD pathogenesis has recently shifted from Aβ plaques to considering smaller,
soluble forms of Aβ assemblies called Aβ oligomers. Oligomers are highly toxic and impair
synaptic function.53 Furthermore, increased oligomer levels are strongly associated with
cognitive dysfunction.53–55 A recent study by Pop and colleagues,56 examined the
accumulation of oligomeric Aβ in the temporal lobe of canines. This study provided
evidence that canines, like humans, experience an increase in toxic oligomers with age.
Vascular Disorders, Cerebrovascular Amyloid Angiopathy

Cerebrovascular amyloid angiopathy (CAA) is the deposition of Aβ in association with the

cerebrovasculature (see Fig. 1D). In dogs with CAA, the blood vessels of the brain typically
contain the shorter, 40 amino acid–long species of Aβ.57–59 The occipital cortex seems to be
particularly vulnerable to CAA in the aged dog brain. Vascular Aβ may compromise the
blood-brain barrier, disrupt vessel wall viability,60 and cause microhemorrhages.61
Aged dogs may also show lacunar infarcts of the caudate nucleus and thalamus with most
dogs showing no causative metabolic, endocrine, or hypertensive disease.62,63 In a
longitudinal study, these lesions were shown to increase in number with advancing age.64
Lacunar infarcts of the caudate nucleus have been induced experimentally in beagle dogs by
proximal middle cerebral artery occlusion.65 The cause of naturally occurring lacunar
infarcts in dogs remains unidentified.
Tau Neuropathology
Unlike humans but like many other animal species, canines do not develop full-blown
neurofibrillary tangles,32,37,39,40 which is the second neuropathologic characteristic of AD.
However, aged dogs show the accumulation of several phosphorylated tau epitopes that are
consistent with AD in humans and observations in aged cats (described later).66 In a study of
cognitively impaired pet dogs that included a variety of breeds, intracellular phosphorylated
tau was observed that was similar to the AD brain.67
Oxidative Damage and Mitochondrial Dysfunction

Aging and the production of free radicals can lead to oxidative damage to proteins, lipids,
and nucleotides that, in turn, may cause neuronal dysfunction and ultimately neuronal death.
In the aging dog, the brain accumulates carbonyl groups, which are a measure of oxidative
damage to proteins.68,69 Carbonyl groups are associated with reduced endogenous
antioxidant enzyme activity or protein levels, including those of glutamine synthetase and
superoxide dismutase (SOD).68,70–72 In addition, increased oxidative damage to proteins can
be measured by the end products of lipid peroxidation (oxidative damage to lipids),
including 4-hydroxynonenal,50,52,72,73 lipofuscin,50 lipofuscinlike pigments,52,73 or
malondialdehyde.68 In addition, oxidative damage to DNA or RNA may be increased in the
aged dog brain.5,50
Oxidative damage may also be associated with behavioral decline in dogs. Increased
oxidative end products in the aged companion dog brain are correlated with more severe
behavioral changes.50,52,69 In laboratory studies of aging beagles, higher protein oxidative
damage (3-nitrotyrosine) and lower endogenous antioxidant capacity (SOD and glutathione-
S-transferase activities) are associated with poorer prefrontal-dependent and spatial
learning.71 Mitochondria are sources of free radicals that damage proteins, lipids, and DNA/
RNA.74 In a study of aged beagles, isolated mitochondria showed increased reactive oxygen
species production in aged animals relative to young animals.75 Thus, aged dogs show
mitochondrial dysfunction and oxidative damage, consistent with humans with age-related
neurologic dysfunction.
Correlates of Brain Aging Found in Lysosomal Storage Diseases

Cross-sectional studies of brain aging are negatively influenced by interindividual variations
in brain size and structure, as well as by differing rates of atrophy. Longitudinal studies may
be limited by repeated access to aged animals and to subject attrition.64 Insight into
mechanisms of brain aging can also be obtained through the study of breeding colonies of
dogs with naturally occurring hereditary metabolic disorders, including mitochondrial
disorders, lysosomal storage diseases, and leukodystrophies, which have clinical,
neuropathologic, and biochemical changes similar to those found in old dogs. These
disorders allow both cross-sectional and longitudinal studies of disease progression in
related animals with short life spans.76,77 For example, more than 40 inherited lysosomal
storage diseases (LSDs) have been identified, with many characterized by progressive
cognitive decline, memory loss, brain atrophy, loss of myelin, and region-specific loss of
neurons as are seen in aging.78,79 Two well-studied diseases are examples of what has been
learned by studying affected dogs. The neuronal ceroid lipofuscinoses (NCLs) are
characterized by seizures, motor dysfunction, impaired vision, progressive cognitive decline,

impaired memory, behavioral problems, brain degeneration, selective neuronal loss that is
most severe in the cerebral cortex, white matter atrophy, neuronal accumulation of protein
and lipid, and premature death.80,81 Both human patients and affected dogs show various
ages of onset, disease course, and neuropathology.80–82 The juvenile-onset form of the
disease, known as Batten disease, has naturally occurring analogous disease in English
setters, Tibetan terriers, and border collies.83 Biochemical analysis of the brain shows that
storage of subunit c of the mitochondrial ATP synthase complex occurs; subunit c is an
essential membrane component of the proton channel of the ATP synthase complex, which
generates ATP by oxidative phosphorylation.81 Although not fully characterized, the
neuronal loss seen in Batten disease is postulated to be caused by mitochondrial dysfunction
and energy-linked excitotoxicity.83 Synaptic loss and glial activation also occur in this
disease, although the mechanism and contribution of these abnormalities to disease
progression are not yet understood.80
The T-maze reversal learning task has been used to evaluate progressive cognitive decline in
the dachshund model of late-infantile NCL, which is caused by a mutation in the gene
encoding the enzyme tripeptidyl-peptidase 1 (TTP1).84 This model system is particularly
interesting because intrathecal administration of TTP1 results in decreased lysosomal

storage.85 It is likely that a better understanding of how mitochondrial dysfunction and
neuronal loss develop in the NCLs, as well as how they may be reversed with therapy, will
shed light on similar mechanisms postulated to occur in brain aging.
Mucopolysaccharidosis type I (MPSI; Hurler syndrome) is another LSD characterized by

progressive cognitive decline, including impaired memory and intelligence, in human
patients.86 Affected humans and dogs show progressive cortical atrophy, ventricular
enlargement, and white matter loss.87 Cardiovascular disease and accumulation of
intracellular Aβ are also described in affected patients.88,89 In human patients with MPSI,
MRI showed that corpus callosum volume and fractional anisotropy correlated with
neuropsychological testing.86 In dogs with MPSI, imaging studies showed corpus callosum
volumes to be smaller in affected dogs compared with unaffected dogs; no cognitive studies
have yet been performed. Similar to the late-infantile NCL, this disease is amenable to either
whole-brain therapy by intrathecal enzyme replacement therapy or to regional gene therapy
allowing for the assessment of therapeutic effect.90,91 When treated with intrathecal alpha-
iduronidase, the enzyme that is deficient in MPSI, corpus callosum volumes in affected dogs
were no longer distinguishable from those in unaffected dogs. These studies indicate the
usefulness of quantitative imaging to study brain atrophy over time as well as the
effectiveness of therapy in ameliorating the atrophy.
NEUROBIOLOGY OF AGING IN THE CAT

Cats are considered to be old, or senior, starting around the age of 7 to 10 years but
consistently after 12 years, depending on the individual animal. Aging cats show several
behavioral changes that can be of concern to a pet owner and that are not related to systemic
illness or disease.92 Whether there is cognitive decline in aging cats as observed in dogs is
still being studied but there are behavioral changes that have been reported clinically.93
There are fewer studies of the aging cat brain compared with aging dogs in the literature,
highlighting the significant gaps in knowledge regarding feline brain aging. Several reviews
have been written describing feline age-associated neurologic disorder and some of those
observations are summarized here.92,93
Neuron Loss and Atrophy

There are several studies suggesting that the caudate nucleus of aging cats is affected by
aging, including reduced neuronal numbers and reduction in the density of synapses.94–97
These losses may lead to impairments in motor function.94 The locus coeruleus, a key
nucleus responsible for producing the neurotransmitter acetylcholine, which is associated
with learning and memory, also shows neuronal losses with age in cats.98
Aβ
Aβ is typically observed in cats more than the age of 10 years,99–103 although there is a
report of 7.5-year-old animal showing Aβ disorder.102 Feline Aβ deposition seems to be
different from that of dogs and humans in several respects. Unlike human and dog brain,
plaques in the cat brain are primarily made up of Aβ1-42 without Aβ1-40 and the peptide is
not posttranslationally modified (suggesting a more rapid turnover) in cats compared with
dogs and humans.66,99 Further, truncated Aβ (AβpN3) was absent in aged cat brain.104
Blood vessels in aging cat brains are positive for Aβ1-40, the shorter more soluble form of
Aβ.66 To our knowledge, there are few reports of the link between behavioral dysfunction
and the extent of Aβ disorder as reported in dogs. Although cats that show signs of
behavioral dysfunction tend to also have Aβ plaques,100 the severity of behavioral changes
does not seem to correlate well with the extent of Aβ disorder.66
Tau Phosphorylation
An interesting feature of the aging cat brain is the detection of phosphorylated tau protein,
which is consistent with reports in human AD.105,106 Cats show multiple isoforms of tau
protein, as do humans.107 Not all studies consistently observe tau neuropathology in
cats101,108,109 and this may be because of methodological challenges. In addition, when
using sensitive immunohistochemical methods, phosphorylated tau is not as frequently
observed as Aβ plaques, but the epitopes on tau that are phosphorylated overlap with those
observed in dogs and humans.66 The morphology of neurons that show an accumulation of
intracellular phosphorylated tau suggests a sprouting response, which is also similar to

human brain.66 Tau phosphorylation is also more frequently associated with the presence of
seizures in aging cats.100
Neuronal Loss in Feline Niemann-Pick Type C Disease and Similarities to AD

Niemann-Pick type C (NPC) disease is another example of how LSDs may contribute to the
understanding of neuronal loss, oxidative stress, Aβ deposition, and tau neuropathology in
the aging brain. NPC disease is caused by dysfunction of either of 2 proteins, NPC1 or
NPC2, which result in lysosomal storage of cholesterol and glycosphingolipids.110 How
dysfunction of these proteins results in the dementia and neuronal loss associated with
disease has been difficult to determine. A feline model of NPC1 disease exists and has been
critical for understanding disease pathogenesis and evaluating therapy.110–115 As disease-

modifying therapies are evaluated, clinicians hope to gain insight into the relative
contributions of each of the following factors in causing cognitive decline and brain atrophy.
Autophagy, the degradation or recycling of damaged intracellular organelles and

aggregated-proteins, is necessary for cellular homeostasis. NPC1 has been implicated in
mediating membrane-tethering events between autophagosomes and late endosomes that
subsequently fuse with lysosomes to degrade their contents.116 When NPC1 is defective,
autophagy is impaired. Because impaired basal autophagy has been found to cause
neurodegeneration,117,118 it is postulated that impaired autophagy in NPC1 disease may
contribute to the observed neuronal loss as a consequence of the buildup of dysfunctional
mitochondria and the accumulation of misfolded proteins, resulting in cell death. Altered
autophagosomal-lysosomal function has similarly been implicated in brain aging.119,120
Oxidative stress and the generation of reactive oxygen species have also been proposed as
contributing factors for neuronal loss in NPC disease.121 In vitro studies showed increased
oxidative stress in cultured neurons and fibroblasts.122 Evaluation of serum from patients
with NPC showed decreased fractions of reduced coenzyme Q10 and decreased Trolox-
equivalent antioxidant capacity.121 Evaluation of plasma and cerebrospinal fluid from
patients and affected cats showed accumulation of cholesterol oxidation products, and, in
cats, these oxysterols decreased in response to a disease-modifying therapy.122
In addition, both NPC1 disease and AD are marked by dementia and abnormal cholesterol
metabolism; however, they also share abnormalities in Aβ processing and the presence of
neurofibrillary tangles.110,123 First, in both affected humans and cats, relative Aβ peptide
distributions differ from those found in unaffected individuals, with lower relative levels of
Aβ1-37, Aβ1-38 and Aβ1-39 in cats with NPC1 compared with controls.124 Second,
neurofibrillary tangles composed of paired helical filaments of phosphorylated microtubular
protein accumulate in NPC disease as they do in AD.110 Third, apolipoprotein E4, the
isoform associated with increased risk for developing AD, has also been found to be
associated with early onset of disease and with increased NPC1 disease severity.123 Other
deficits seen in NPC1 disease, including peroxisomal dysfunction,125 abnormal sphingosine
metabolism,126 neuroinflammation,127 and induction of apoptosis,128 may also contribute to
changes seen in the aging brain.129
CLINICAL IMPLICATIONS OF BRAIN AGING IN DOGS AND CATS

Laboratory-based studies of cognition in beagles suggest that there are age-dependent
functional changes related to brain disorders. In the clinic, owners of geriatric dogs
frequently report behavioral changes.130–132 Some of these behavioral changes may be
linked to systemic illness or other health issues (including sensory decline). When ruled out,
a subset of older dogs shows evidence of behavioral changes that are now considered to be
signs of canine cognitive dysfunction (CCD). The original reports of CCD were by Ruehl
and colleagues133 in the mid 1990s and several reports followed, along with the
development of new tools to detect CCD in pet dogs.6,7,93,134,135 CCD has been linked to
brain pathology in pet dogs.20,136,137 There are reports that CCD can be reduced in aging
dogs through treatment with various pharmaceuticals (eg, Anipryl),134 by dietary

intervention using a prescription diet (B/D diet Hills Pet Nutrition134; the same diet used in
laboratory studies showing a benefit to cognition and neuropathology138), and to
immunotherapy using anti-Aβ approaches.139 In cats, there is less evidence of a form of

feline cognitive dysfunction syndrome but evidence is accumulating that a similar
phenomenon can occur.66,92,93,100,140
SUMMARY
Aging dogs and cats show features of brain disorders that can be similar to human aging and
AD. Neuropathologic changes with age may be linked to signs of cognitive dysfunction both
in the laboratory and in a clinic setting. Less is known about cat brain aging and cognition
and this represents an area for further study. Neurodegenerative diseases such as LSDs in
dogs and cats also show similar features of aging, suggesting some common underlying
pathogenic mechanisms and also suggesting pathways that can be modified to promote
healthy brain aging.
Acknowledgments
The authors are grateful to Virginia Price, DVM, and her stories of Martha and donation of her tissue for research.
We thank Judianne Davis-Van Nostrand and Dr William Van Nostrand at Stony Brook University in New York for
help with collecting tissue for the study. Ms Katie McCarty collected the Aβ immunostaining data for Martha.
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of
Health under award number R01AG031764 (E. Head) and R01NS073661 and P40-02512 (C.H. Vite, Mark
Haskins), and the Ara Parseghian Medical Research Foundation (C.H. Vite). The content is solely the responsibility
of the authors and does not necessarily represent the official views of the National Institutes of Health.
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KEY POINTS
• Brain atrophy, neuron loss, decreased neurogenesis, and oxidative stress but few
tau-associated disorders are observed in aging dog brains.
• Cerebrovascular pathology can be extensive in canine brain aging.
• β-Amyloid protein, associated with Alzheimer disease in humans, is increased

with age in the dog brain and is linked to signs of learning and memory
impairments.
• Lysosomal storage diseases in dogs are associated with similar types of

neuropathology as are observed with aging and Alzheimer disease.
• Few studies describe the neurobiology of aging in cats but interesting

similarities and differences from dogs have been reported.
• Feline Niemann-Pick type C disease has several neuropathologic and clinical

similarities to Alzheimer disease.
Fig. 1.
Aβ immunostaining (brown) in the brain of a 14-year-old border collie (Martha) with signs
of cognitive dysfunction syndrome. Aβ was detected using the 6E10 antibody that binds Aβ
1 to 16. (A) Low-power magnification (1.5×) of extensive Aβ deposition in the

hippocampus. (B) Aβ is primarily found in the outer molecular layer of the dentate gyrus,
which contains neuron terminals originating from the entorhinal cortex (4×). (C) The
prefrontal cortex also shows extensive Aβ deposition that appears most dense in layers II
and V of the cortex and is less apparent in the white matter (1.5×). (D) At high
magnification (4×), the differential deposition of Aβ in the 6 cortical layers can be seen as
well as extensive white matter cerebral amyloid angiopathy (arrow). Sections have been
counterstained with cresyl violet (blue).
Fig. 2.
Aging and canine cognitive dysfunction in a border collie (Martha). (A) Martha competing
in sheep dog trials when she was young, and (B) still active around the age of 10 years. As
she reached 11 years of age she struggled to complete commands issued by her owner (C).
At 14 years of age, Martha was generally in good health except for arthritis but would not
make eye contact with her owner (D).
Table 1
Comparison of dog and cat neurologic neurodegenerative features

Neurobiological Outcome Measures Canine Feline NCL or MPSI NPC Disease

Brain atrophy Yes NA Yes Yes
β-Amyloid Yes Yes Yes Yes
Tau Yes Yes NA Yes
Cerebral amyloid angiopathy Yes Yes NA NA
Infarcts Yes NA NA NA
Vascular disease Yes NA Yes NA
Lipofuscin accumulation Yes Yes Yes NA
Caspase activation Yes NA Yes Yes
DNA fragmentation Yes NA NA NA
Neuron loss: hippocampus Yes NA Yes Yes
Neuron loss: caudate NA Yes Yes Yes
Neuron loss: locus coeruleus Yes Yes NA NA
Neuron loss: Purkinje cerebellar cells Yes NA Yes Yes

White matter degeneration Yes NA Yes Yes
Inflammation Yes NA Yes Yes
Oxidative damage Yes NA Yes Yes
Gliosis Yes NA Yes Yes
Abbreviations: MPSI, mucopolysaccharidosis type I; NA, not available; NCL, neuronal ceroid lipofuscinoses; NPC, Niemann-Pick type C.

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Aging in the Canine and Feline Brain

β-Amyloid; Cat; Dog; Cognitive dysfunction; Neuron loss; Tau

© 2014 Elsevier Inc. All rights reserved.

NEUROBIOLOGY OF AGING IN THE DOG

Selective Neuron Loss

impaired show a significant reduction in noradrenergic neurons. Reduced neurogenesis in

Senile Plaques (β-Amyloid) in Dogs

Vascular Disorders, Cerebrovascular Amyloid Angiopathy

Cerebrovascular amyloid angiopathy (CAA) is the deposition of Aβ in association with the

Oxidative Damage and Mitochondrial Dysfunction

aged dog brain.5,50

Correlates of Brain Aging Found in Lysosomal Storage Diseases

characterized by seizures, motor dysfunction, impaired vision, progressive cognitive decline,

interesting because intrathecal administration of TTP1 results in decreased lysosomal

Mucopolysaccharidosis type I (MPSI; Hurler syndrome) is another LSD characterized by

NEUROBIOLOGY OF AGING IN THE CAT

observations are summarized here.92,93

Neuron Loss and Atrophy

intracellular phosphorylated tau suggests a sprouting response, which is also similar to

Neuronal Loss in Feline Niemann-Pick Type C Disease and Similarities to AD

critical for understanding disease pathogenesis and evaluating therapy.110–115 As disease-

Autophagy, the degradation or recycling of damaged intracellular organelles and

CLINICAL IMPLICATIONS OF BRAIN AGING IN DOGS AND CATS

dogs through treatment with various pharmaceuticals (eg, Anipryl),134 by dietary

immunotherapy using anti-Aβ approaches.139 In cats, there is less evidence of a form of

11. Gonzalez-Soriano J, Marin Garcia P, Contreras-Rodriguez J, et al. Age-related changes in the

a canine model of aging. J Neurosci. 2004; 24(38):8205–13. [PubMed: 15385603]

amyloidogenesis in canines. Neurobiol Aging. 2012; 33(1):108–20. [PubMed: 20434811]

91. Chen A, Vogler C, McEntee M, et al. Glycosaminoglycan storage in neuroanatomical regions of

disease type C. Curr Biol. 2001; 11(16):1283–7. [PubMed: 11525744]

storage diseases. Autophagy. 2007; 3(3):259–62. [PubMed: 17329960]

Exp Neurol. 2003; 184(2):887–903. [PubMed: 14769381]

tau-associated disorders are observed in aging dog brains.

• Cerebrovascular pathology can be extensive in canine brain aging.

• β-Amyloid protein, associated with Alzheimer disease in humans, is increased

• Lysosomal storage diseases in dogs are associated with similar types of

• Few studies describe the neurobiology of aging in cats but interesting

• Feline Niemann-Pick type C disease has several neuropathologic and clinical

1 to 16. (A) Low-power magnification (1.5×) of extensive Aβ deposition in the

Comparison of dog and cat neurologic neurodegenerative features

Neurobiological Outcome Measures Canine Feline NCL or MPSI NPC Disease

β-Amyloid Yes Yes Yes Yes

Tau Yes Yes NA Yes

Cerebral amyloid angiopathy Yes Yes NA NA

Vascular disease Yes NA Yes NA

Lipofuscin accumulation Yes Yes Yes NA

Caspase activation Yes NA Yes Yes

DNA fragmentation Yes NA NA NA

Neuron loss: hippocampus Yes NA Yes Yes

Neuron loss: caudate NA Yes Yes Yes

Neuron loss: locus coeruleus Yes Yes NA NA

Neuron loss: Purkinje cerebellar cells Yes NA Yes Yes

White matter degeneration Yes NA Yes Yes

Inflammation Yes NA Yes Yes

Oxidative damage Yes NA Yes Yes

Gliosis Yes NA Yes Yes